The five year survival in ovarian cancer is very low, mostly because the disease is usually detected late, when the tumors have spread outside of the ovaries, in the peritoneal cavity. Delayed progress in the discovery and implementation of a more effective treatment is partly due to the paucity of preclinical models that recapitulate human disease and that can be used to develop and test new treatments. In this proposal we present one such mouse model and our plans to use it for learning more about the immunobiology and immunotherapy of ovarian cancer. Our recently developed transgenic mice express human mucin 1 (MUC1), a glycoprotein important in the development and therapy of ovarian cancer. More than 80% of all epithelial ovarian tumors overexpress MUC1, an oncoprotein involved in various signaling pathways, impacting cell survival through alterations of cell growth, proliferation and metastasis. MUC1 is also a tumor-associated antigen and a target for immune therapy and cancer vaccine development. By combining the MUC1 transgenic (Tg) mice with the previously reported LSLKrasG12D/+PtenloxP/loxP mice, we generated triple Tg MUC1+/-LSLKrasG12D/+PtenloxP/loxP (MUC1KrasPten), which develop MUC1+ ovarian tumors subsequent to Cre-encoding adenovirus (AdCre) injection in the mouse ovarian bursa. Our recent studies from triple Tg MUC1KrasPten mice showed that despite the histomorphologic similarities, there are several notable phenotypic differences between the ovarian tumors that develop in triple (MKP) and double (KP) transgenic mice: the MKP tumors are smaller at the primary (ovarian) site, generate more loco-regional metastases and show increased accumulation of immune suppressive T cells (Tregs). In addition, the tumors develop in a highly inflammatory environment, dominated by VEGF, COX2 overexpression and PGE2 accumulation. Based on these observations, we hypothesize that MUC1 accelerates loco-regional tumor growth and may link inflammation with ovarian tumor development. To test this hypothesis, we propose the following aims: 1.To define the mechanisms of MUC1 upregulation during ovarian tumor initiation and its consequences on EMT and tumor metastasis. 2. To evaluate MUC1 roles in loco-regional inflammation. 3. To test in vivo efficacy of MUC1-based vaccines. Our work combines in vivo testing of novel therapies, using a novel a highly versatile triple Tg animal model of ovarian cancer, with comprehensive in vitro examination of mechanistic pathways involved in cancer metastasis and loco-regional inflammation. Results from our studies may advance our understanding of the MUC1 oncogene in disease pathogenesis and provide the rationale for future immunotherapy trials in ovarian cancer. PUBLIC HEALTH RELEVANCE: The five year survival in ovarian cancer is very low, mostly because the disease is usually detected late, when the tumors have spread outside of the ovaries, in the peritoneal cavity. Despite improvements in current treatments, which typically combine surgery and chemotherapy, the tumor invariably recurs and the patients succumb to loco-regional metastases. We focus here on an ovarian tumor-associated antigen and oncoprotein called mucin 1 (MUC1) and will test the hypothesis that MUC1 plays a key role in tumor metastasis and that MUC1-based vaccines may provide therapeutic benefit in ovarian cancer.